Among all mental illnesses, schizophrenia is one that has been often related to prefrontal cortex. The long-range objective of this Center is to elucidate the prefrontal cortical mechanisms that are particularly relevant to schizophrenia. The underlying hypothesis of this Center, that the disordered thought process of schizophrenics reflects dysfunction in prefrontal circuits, has only grown stronger over the years, largely as a consequence of the application of powerful methodologies and neurobiological concepts. The present CNMD is constituted of seven projects - altogether bringing a wide diversity of molecular, developmental, physiological, pharmacological, and behavioral techniques to bear on the primate - nonhuman and human - cerebral cortex. A team of investigators representing six institutions and multiple departments throughout Yale University have joined together in this endeavor to mount the following projects: (1) single cell recordings in normal monkeys performing working memory and other cognitive tasks; (2) comparative study of smooth pursuit tracking and cognitive deficits in schizophrenic patients and monkeys with prefrontal lesions; (3) comprehensive cytochemical, immunohistochemical, electronmicroscopic and local circuit analyses designed to dissect structural and/or biochemical cortical components in monkey, normal human and schizophrenic cortex; (4) molecular analysis of the cortical dopamine system in monkeys and humans including comprehensive description of the D1A, DIB (D5), D2A, D3 and D4 dopaminergic receptor subtypes, as well as radioautographic localization, in situ hybridization of receptor bearing neurons and detection of mRNAs for the various cortical receptors; (5) evaluation of the biochemical consequences of acute and chronic antipsychotic drug treatment in the non-human primate using micro-dialysis; (6) evaluation of the effects of D1 and D2 agonists and antagonists alone and in combination with excitatory amino acid transmitters on cognitive, motor and spontaneous behavior in rhesus monkeys and in healthy volunteers; and (7) magnetic resonance imaging of cortical activation in human subjects performing working memory tasks. A focused attack on cerebral cortical mechanisms should provide an integrative view of schizophrenia and suggest specific approaches for ameliorating its negative as well as positive symptoms.